Dampening of an immunodominant epitope of an antigen for use in plant, animal and human vaccines and immunotherapies

The present invention provides a vaccine that can be administered to a mammal to cause immunoprotection in the mammal against a pathogenic organism that has an immunodominant epitope. The vaccine includes a modified form of the antigen in which the immunodominant epitope is located. In this modified form, the immunodominant epitope is immunodampened by any of a number of techniques. Examples of immunodampening techniques include addition of N-linked glycosylation sites, change of the net charge on the epitope, and substitution with a tolerated sequence. The vaccine also includes a pharmacologically acceptable carrier.

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Claims

1. An immunogenic composition, comprising:

a modified form of a native antigen of a pathogen, the native antigen having disposed at a position thereon an immunodominant epitope comprising a plurality of amino acids, said modified form of the native antigen having a modified epitope at the position of the immunodominant epitope of the native antigen, said modified epitope having been immunodampened so as to substantially redirect an immune response away from the modified epitope and toward a different part of said modified form of the native antigen; and
a pharmacologically acceptable carrier.

2. The composition of claim 1, wherein said modified form of the native antigen has a modified amino acid sequence that includes one or more N-linked glycosylation signals not present in the native antigen.

3. The composition of claim 1, wherein said carrier comprises a pharmacologically acceptable saline buffer.

4. The composition of claim 1, wherein said modified epitope has been immunodampened by addition of carbohydrate moieties.

5. The composition of claim 1, wherein said modified epitope is immunodampened by an alteration of amino acids.

6. The composition of claim 5, wherein said alteration of amino acids comprises an amino acid substitution.

7. The composition of claim 5, wherein said alteration of amino acids produces an altered set of amino acids against which a humoral response is not substantially produced in a human.

8. The composition of claim 7, wherein said altered set of amino acids comprise a linear human B-cell epitope.

9. The composition of claim 5, wherein said immunodominant epitope has a native charge and said modified epitope has a modified charge that differs from the native charge of the immunodominant epitope.

10. The composition of claim 5, wherein said alteration comprises deletion of one or more amino acids.

11. The composition of claim 1, wherein said immunodominant epitope includes a binding site for at least one other molecule, and wherein said composition additionally comprises said at least one other molecule irreversibly bound to said immunodominant epitope.

12. The composition of claim 11, wherein said other molecule comprises an antibody directed against said immunodominant epitope.

13. The composition of claim 1, wherein said pathogen is HIV-1.

14. The composition of claim 13, wherein said native antigen is gp120/160.

Referenced Cited
U.S. Patent Documents
5041376 August 20, 1991 Gething et al.
5585250 December 17, 1996 Garrity et al.
Other references
  • S. Olofsson, et al.; Vaccines 93.; pp. 183-187; "Peripheral Carbohydrate structures engaged in regulation of antigenic properties of HIV-1 gp120". A. Bolmstedt, et al.; Journal of General Virology; vol. 73, No. 12, Dec. 1992, pp. 3099-3105; "Carbohydrate determinant NeuAc-Galbeta(1-4) of N-linked glycans modulates the antigenic activity of human immunodeficiency virus type 1 glycoprotein gp120". P. Simmonds, et al.; Journal of Virology; vol. 164, No. 12, Dec. 1990; pp. 5840-580; "Analysis of sequence diversity in hypervariable regions of the external glycoprotein of human immunodeficiency virus type 1". H. Kohler, et al.; Journal of Acquired Immune Deficiency Syndromes; vol. 5, No. 11, Nov. 1992; "Clonal Dominance: Cause for a limited and failing immune response to HIV-1 infection and vaccination". R. Garrity, et al.; Aids Research and Human Retroviruses; vol. 10, No. SUP1; Aug. 1993; "Introduction of potential N-linked glycosylation sites into the V3 domain of HIV-1 gp120: Effects on virus viability, antigenicity and immunogenicity".
Patent History
Patent number: 5853724
Type: Grant
Filed: Dec 13, 1996
Date of Patent: Dec 29, 1998
Assignee: The United States of America as represented by the Department of Health and Human Services (Washington, DC)
Inventors: Robert R. Garrity (Middletown, MD), Peter L. Nara (Frederick, MD), Jaap Goudsmit (Amsterdam)
Primary Examiner: Lynette F. Smith
Law Firm: Knobbe, Martens, Olson & Bear, LLP
Application Number: 8/764,575
Classifications
Current U.S. Class: 424/1841; 424/1881; 424/2041; 424/2881; Glycoprotein, E.g., Mucins, Proteoglycans, Etc. (530/395)
International Classification: A61K 3900; A61K 3921; C07K 100; C07K 1400;